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Lung transplants can be lifesaving for patients with end-stage lung diseases such as cystic fibrosis, COPD, pulmonary fibrosis, sarcoidosis, and pulmonary hypertension. Wait times for a lung vary from days to years, depending on a complex set of circumstances. In the US, 1400 adults and children await lungs at any given time. Less than a third of them will get one.
Position on the wait list is based on several factors: medical urgency, compatibility with an available lung, distance from the donor hospital, and pediatric status, according to the United Network for Organ Sharing.
An easily tested indication of whether a person’s body will accept a transplanted organ is the ABO blood type. It doesn’t have to match between donor and recipient, but it must be compatible. The A and B antigens (cell surface molecules) are sugars that are attached to proteins and fats on a cell’s surface. The blood type is a single-gene trait.
Canadian researchers have tested a way to strip donor lungs from type A individuals of the A antigens that make them type A, using enzymes. Denuding the lungs essentially creates an “ABO-agnostic organ” that could, theoretically for now, nestle into the chest of a person with any ABO blood type and not induce rejection. The idea has been around for awhile without much success, but using a new pair of enzymes, discovered in the human gut microbiome in 2019, seems to improve on past attempts.
“The treatment described here could further expand the pool of universal donor organs from the current 55% (blood group O donors) to over 80%. This strategy may greatly improve access and fairness of organ allocation,” Aizhou Wang and colleagues from the University of Alberta write in Science Translational Medicine. The strategy could be applied to organs other than lungs. More than 100,000 individuals in the US await organs.
The ABCs of ABO Blood Types
The challenge in matching donor organ to recipient comes down to the interaction between the recipient’s immune system’s antibodies that act against antigen molecules – proteins or carbohydrates – on a cell (or virus’s) surface. Type A red blood cells have antigen A, type B has antigen B, type AB has both, and type O, neither.
People with type O blood make antibodies against the A and B antigens, and so they can only receive lungs from a donor who had type O blood, with no A or B antigens festooning the red blood cell surfaces. Their bodies would make antibodies against antigens A or B. Because of this restriction, being type O elevates a recipient’s risk of death while awaiting a donor lung by 20%. But people of any ABO type could use an organ that is type O. That’s why type O organs are in high demand.
The A and B alleles (gene variants) are codominant, meaning that both can be present, in an individual who is type AB. A and B are completely dominant to O, which is recessive. Also, types A and B can be heterozygous – that is, one chromosome that carries the gene encodes the A antigen, but the other is more or less a blank. This means that a person who is a heterozygote (aka carrier) for type A and another individual who is a heterozygote for type B can together have kids who are of any ABO type – A, B, AB, or O.
Stripping Antigens from Donor Lungs Creates Type O
Treating lungs from individuals with type A blood with a pair of enzymes (the unpronounceable FpGalNAc deacetylase and FpGalactosaminidase, called Azymes for short) that removes the A antigens from lung cells converts the organ to the universal type O. This “less is more” strategy, called ex vivo lung perfusion (EVLP), changes the phenotype (trait) of the donor lung cells, not the underlying genotype. EVLP cloaks the organ from the recipient’s immune system.
The researchers tested the technique first on human red blood cells and pieces of aorta, then on disembodied lungs. Results were encouraging.
A very dilute enzyme brew removed 99% of the A antigens from the red blood cells and 90% from the aorta. On 8 lungs, EVLP plucked off and washed away 97% of the A antigens within 4 hours. And the treated lungs weren’t inflamed or otherwise damaged.
Next the investigators set up a situation that mimicked rejection of a lung transplant: they used plasma from a type O individual, which would contain antibodies against both A and B antigens. They applied the type O plasma to three lungs stripped of their A antigens. And it worked! The stand-in for a type O recipient didn’t launch an antibody attack against the doctored lungs, nor produce complement, an immune system chemical that triggers inflammation. But the type O plasma did indeed attack control type A lungs that hadn’t been enzyme-treated.
The experiments also revealed that the crucial players in organ rejection are the epithelial and endothelial cells of the lungs – that is, the outside and inside linings rather than the tiny air sacs where gas exchange occurs.
The researchers are following up their work on the disembodied human lungs with studies in mice, for preclinical indications of safety and efficacy. Next step, clinical trials. And then maybe more people in need of lungs will find them.